Mir-223 Is Dispensable for the Onset of Acute Myeloid Leukemia
Bibliographic record
Abstract
Abstract Abstract 501 The functional roles of microRNAs in the development of acute myeloid leukemia (AML) are not yet clear. Due to its myeloid-specific expression, miR-223 has been one of the most-investigated miRNAs in normal and malignant hematopoiesis. However, the role of miR-223 in myeloid differentiation is not completely understood, as contradicting data exists. Genetic depletion of miR-223 led to a significant increase of myeloid progenitor cells as well as circulating hyperreactive neutrophils. Here, we investigate the role of miR-223 in the development of AML in vivo, using retroviral overexpression models of Hoxa9 with Meis1 or MN1 as two potent models of leukemic transformation in a miR-223+/+ or miR-223−/− background. In contrast to the observed high level expression of miR-223 in human CD34- bulk AML cells (p=0.0106), we could show that miR-223 was dispensable for the development of AML and did not impact on either the leukemic stem cell frequency nor the AML cell phenotype in Hoxa9-Meis1 AML cells. While these findings reveal that miR-223 is not necessary for leukemic transformation in highly aggressive AML models, we became interested if miR-223 functions rather as modulator of disease progression, especially at the early development of AML. Therefore, we investigated the role of miR-223 with regards to differentiation and self-renewal in two preleukemic model systems by retrovirally infecting miR-223−/− and miR-223+/+ BM cells with AML1-ETO and Hoxa9 respectively. Characterization of these models demonstrated that miR-223 expression is a determinant of differentiation, as miR-223−/− preleukemic cells exhibit a significant lower Mac-1 expression (p=0.0003). However, in contrast to normal miR-223−/− BM cells, which show a significantly higher colony forming capacity in methylcellulose compared to miR-233+/+ BM cells, the colony forming capacity of miR-223−/− or miR-223+/+ preleukemic cells did not significantly change. These findings demonstrate that miRNA miR-223 is hierarchically expressed in AML cells, and functionally link miR-223 to impaired differentiation rather than increased self-renewal in the initiation of AML. This indicates that miR-223 is more likely a fine tuner of leukemic development than a potent tumor suppressor or oncogenes as suggested in the literature. However, it still remains to be shown if the presence of miR-223 influences the susceptibility of preleukemic cells to convert into leukemia initiating cells. Disclosures: No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".